Aetiology

Colorectal cancer represents a complex interaction of genetic and environmental factors.

Genetic factors:

The majority of colorectal cancers are sporadic rather than familial, but after increasing age, family history is the most common risk factor.

For individuals with one affected first-degree relative, the relative risk of developing colorectal cancer is 2.24.[16] This increases to 3.97 with two affected first-degree relatives.[16] Siblings and children of patients with colorectal polyps are also at increased risk for developing colorectal cancer (odds ratio 1.40, 95% CI 1.35 to 1.45).[17]

Family cancer syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome, are associated with 2% to 5% of all colon cancers.[18][19] See Familial adenomatous polyposis syndrome.

Environmental factors:

More than half (55%) of colorectal cancers in the US are attributable to potentially modifiable risk factors.[6]​​

Obesity confers an increased risk of developing colon cancer compared with normal-weight individuals, and is associated with a greater risk of dying from the disease.[20][21]​​​​​​[22][23][24]​​​​​​​ In one systematic review, obesity was associated with an increased risk of early-onset colorectal cancer (under 50 years) among women.[25]​ While some studies have reported a significant reduction in colorectal cancer risk in patients with obesity who underwent bariatric surgery, others have failed to demonstrate a significant impact.[24][26][27][28][29]​​[30]​​​​​​​​​​

Obesity, high calorie intake, and physical inactivity are probably synergistic risk factors for the development of colorectal cancer.[20][22][31][32]​ Studies have shown that a high intake of red and processed meat is associated with an increased risk of colorectal cancer.[33][34][35]​ Some evidence suggests that high carbohydrate intake may increase the risk of colorectal cancer in men.[36]

Most studies (but not all) suggest an inverse relationship between dietary fibre intake and colorectal cancer risk.[37][38][39][40]​​​​​ [ Cochrane Clinical Answers logo ] ​​​ Cigarette smoking, moderate to heavy alcohol consumption, and low vitamin D are also associated with increased risk of colorectal cancer.[7][41][42][43][44][45][46]​​[47]​​​​[48]

Microplastics may also increase the risk of colorectal cancer.[10]

Pathophysiology

Colorectal cancers arise from dysplastic adenomatous polyps in the majority of cases.[49]​ There is a multi-step process involving the inactivation of a variety of tumour-suppressor and DNA repair genes, along with simultaneous activation of oncogenes. This confers a selective growth advantage to the colonic epithelial cell, and drives the transformation from normal colonic epithelium to adenomatous polyp to invasive colorectal cancer.[50]

There are three main pathways of genomic instability that lead to colorectal cancer: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways. The CIN pathway, characterised by loss of heterozygosity and aneuploidy, accounts for the vast majority of colorectal cancer cases (65% to 70% of sporadic colorectal cancer).​[49][51]

MSI is a molecular fingerprint of the deficient mismatch repair (MMR) system that characterises around 15% of colorectal cancers.[49] MSI status predicts response to 5-fluorouracil and may also determine responsiveness to other colorectal treatments such as immunotherapy. Identifying deficient MMR has an important impact on patient outcomes and management.[52] 

CIMP is a subset of colorectal cancers that occur via the epigenetic instability pathway, but are characterised by hypermethylation of promoter CpG island sites resulting in the inactivation of tumour suppressor genes.​[49][53]

Adenomatous polyposis coli (APC) tumour suppressor gene

Germline mutations underlie the inherited colon cancer syndromes, whereas sporadic cancers arise from a step-wise accumulation of somatic genetic mutations. A single germline mutation in the adenomatous polyposis coli (APC) tumour suppressor gene is responsible for the dominantly inherited syndrome familial adenomatous polyposis.[54]​ Clinical expression of the disease is seen when the inherited mutation of one APC allele is followed by a second hit mutation or deletion of the second allele. APC mutations are also frequently observed in sporadic adenomas (30% to 70%) and sporadic tumours (72%), suggesting that loss of APC function is a crucial early event in colorectal cancer tumourigenesis.

APC is a tumour suppressor gene that regulates β-catenin.[55]​ Loss of APC function leads to accumulation of β-catenin, which leads to the activation of Wnt signalling and stimulation of cell growth and proliferation.[49]​ KRAS mutation leading to KRAS activation is frequently the next step in the CIN pathway, followed by mutations in the TGFβ, P53, and PIK3CA pathways.[51]

One systematic review and meta-analysis evaluated the prevalence of KRAS and BRAF mutations in patients with metastatic colorectal cancer.[56]​ Among 6699 patients evaluated, 28% of patients had KRAS mutation and 6% of patients had BRAF mutation. The BRAF mutation was most common in patients with right-sided metastatic colorectal cancer.[56] The median global prevalence of KRAS mutation has been reported as 38% (range, 13.3% to 58.9%) and that of the KRAS G12C mutation as 3.1% in another systematic review.[57]

Metastases

Spread of colorectal cancer is to local lymph nodes via enteric venous drainage to the liver and haematogenously to the lungs and, less commonly, to bone and brain.​[58]​ Liver metastasis is common and is observed in around 25% to 30% of patients.[59]

Classification

American Joint Committee on Cancer TNM staging system (8th Edition)[2]

The American Joint Committee on Cancer (AJCC) staging system describes the extent of disease based on the following anatomic factors: size and extent of the primary tumour (T); regional lymph node involvement (N); and presence or absence of distant metastases (M). Nonanatomic prognostic factors (e.g., tumour grade, biomarkers) may be used to supplement the staging of certain cancers.

Use of this content is subject to our disclaimer